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Sinteza derivatov 4-fenetil-1-(prop-2-in-1-il)piperidina s hidroksi in karbamatno skupino kot zaviralcev monoamin oksidaz in holin esteraz = Synthesis of 4-phenethyl-1-(prop-2-yn-1-yl)piperidine derivatives containing hydroxyl and carbamate groups as inhibitors of monoamine oxidases and cholinesterases : enoviti magistrski študij farmacija : Uniform Master's Study Programme PharmacyMazej, TjašaAlzheimerjeva bolezen je progresivna nevrodegenerativna motnja, ki jo spremlja izguba spomina, vedenjske spremembe in upad kognitivnih funkcij. Z več patofiziološkimi mehanizmi pogojen nastanek ... bolezni nakazuje na smiselnost načrtovanja ligandov s hkratnim delovanjem na več terapevtskih prijemališč. Med aktualnimi in terapevtsko zanimivimi tarčami so encimi monoamin oksidaze (MAO) in holin esteraze (ChE). Na podlagi že znanih zaviralcev teh encimov smo načrtovali in sintetizirali nove zaviralce z dvojnim delovanjem (na MAO in ChE) ter ovrednotili vpliv strukturnih modifikacij na njihovo delovanje. Sintetizirali smo enajst derivatov 4-fenetil-1-(prop-2-in-1-il)piperidina, ki smo jim določili zaviralno delovanje na humani acetilholin in butirilholin esterazi (hAChE in hBChE) ter humani monoamin oksidazi A in B (hMAO-A in hMAO-B). Pri sintezi smo izhajali iz piperidin-4-karboksilne kisline, ki smo jo zaščitili v obliki terc-butil karbamata ter jo preko Weinrebovega amida reducirali do aldehida. Temu je sledila Wittigova reakcija do alkena, redukcija dvojne vezi, odščita karbamata in N-alkiliranje s propargil bromidom do ustreznih derivatov 4-fenetil-1-(prop-2-in-1-il)piperidina. Metoksi derivate smo nadalje z BBr3 odščitili do fenolov, ki smo jih z reakcijo s fenil izocianatom ali N-etil-N-metilkarbamoil kloridom pretvorili v končne karbamate. Vsi sintetizirani derivati so delovali zaviralno na hMAO-B, pri čemer so močnejše delovanje imele spojine z 1,4-disubstitucijo in večjimi hidrofobnimi substituenti. Skupna vsem spojinam je bila propargilaminska skupina, ki najverjetneje tvori kovalentno vez s kofaktorjem encima. Za zaviranje BChE je bila nujna prisotnost karbamatne skupine. Sintetizirali smo tri zaviralce z dvojnim delovanjem (27, 28 in 29), izmed katerih je spojina 29 (IC50 (hBChE) = 4,30 [mikro]M, IC50 (hMAO-B)= 8,45 [mikro]M) najbolj obetavna za nadaljnjo optimizacijo. Spojina 29 je namreč strukturni analog potrjenih kovalentnih zaviralcev MAO-B, njeno časovno odvisno zaviranje BChE pa nakazuje na kovalenten mehanizem delovanja.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [T. Mazej], 2021Language - slovenianCOBISS.SI-ID - 54884611
Author
Mazej, Tjaša
Other authors
Sova, Matej, 1979-
Topics
Alzheimerjeva bolezen |
Nevrodegenerativne bolezni |
Zdravljenje |
Wittigova reakcija |
zaviralci |
holin esteraze |
monoamin oksidaze |
4-fenetil-1-(prop-2-in-1-il)piperidin
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Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Mazej, Tjaša | ![]() |
Sova, Matej, 1979- | 25490 |
Source: Personal bibliographies
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